Heparin, heparin salts and heparin complexes, referred to as “heparin” herein, are used broadly in healthcare as blood anticoagulants, antithrombotic agents and coating agents for medical devices. Heparin salts are also used as starting materials to produce low molecular weight heparin, e.g. Fragmin® (Dalteparin Sodium) [WO 80/01383]. Heparin can be extracted from animal tissues and organs and typically contains several biologically derived impurities such as proteins and glycosoaminoglycans such as Dermatan Sulfate. Numerous extraction processes have been developed, e.g. those disclosed in U.S. Pat. Nos. 2,571,679, 2,954,321, 3,337,409, 6,232,093B1 and references cited therein.
To produce the solid form of heparin, in a typical heparin manufacturing and purification process, heparin is precipitated from its water solution with a large volume of a water miscible organic solvent, e.g., ethanol [U.S. Pat. Nos. 2,571,679, 2,954,321], methanol [U.S. Pat. Nos. 2,884,358, 2,797,184, 3,337,409], acetone [U.S. Pat. No. 2,954,321] and the like. The precipitated heparin is dehydrated with a water miscible solvent or collected by filtration, and thereafter dried under vacuum mostly at about 40-75° C. Other drying methods are also used to dry the heparin precipitate as a reconstituted paste in water followed by freeze-drying, e.g. lyophilization [U.S. Pat. No. 3,817,831].
A method of spray drying of a heparin solution was disclosed in a Chinese patent application, CN 1218058A (published on 1999-06-02). By atomizing the heparin solution and drying in hot air entering the spray dryer at 190-200° C., a dry powder was obtained with a specific activity of 128 u/mg.
Inherent problems exist with the method to produce a solid form of heparin in a conventional process. The most significant among these are, excessive use of potentially dangerous and flammable organic solvents, requirement of precise vacuum and temperature control during the drying process, requirement of multiple process stages that include precipitating, drying, milling, and re-drying steps, requirement of extremely long process cycle-times, requirement of high capital and operating costs, requirement of relatively long time of labor, requirement of frequent cleaning of spray nozzles, significant product losses due to handling and entrainment, and potentially adverse quality impact on this heat sensitive heparin product. Typically, in order to preserve anticoagulant properties (potency), the process temperatures cannot exceed 100° C. reach for prolonged times especially during drying stages.
Single or double drum dryers are widely used in chemical and pharmaceutical industries. These drum dryers are used for processing solutions to produce solid products in one operation, e.g. inorganic salts [U.S. Pat. No. 2,034,599], tertiary amine oxide [U.S. Pat. No. 3,330,327] and polysaccharides [U.S Pat. No. 6,485,945]. A double-drum dryer consists of two counter or co-rotating drums that are heated from the inside by steam or other suitable hot fluids. In a double drum dryer, a solution to be dried is loaded into the nip between the drums and squeezed into a thin layer on drum surfaces where it is dried by the hot drum surfaces. Knives scrape off the dried solid and collected in a hopper for further downstream processing. It can be operated under vacuum for temperature-sensitive chemicals. The residence time of this drying process is very short and takes just a few seconds. This is particularly beneficial to heat sensitive products. The drying process can be run in batches, semi-continuous or continuous modes.